Regulation of the paracrine angiogenic function of cardiac myocytes by cardiomyoc

心肌细胞旁分泌血管生成功能的调节

基本信息

批准号：
7992888
负责人：
WADIH ARAP
金额：
$ 39.5万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7992888
关键词：
Adult Aerobic Exercise Angiotensin II Antineoplastic Agents Area Blood Vessels Blood capillaries Cancer Patient Cardiac Cardiac Myocytes Cardiomyopathies Cardiotoxicity Cell Proliferation Cell surface Clinical Complex Coronary Data Development Dilatation - action Endothelial Cells Equilibrium Etiology Exercise Extracellular Matrix Growth Heart Heart Hypertrophy Heart failure Human Hypertrophy Knock-out Knockout Mice Lead Life Link Mediating Mediator of activation protein Modeling Molecular Muscle Cells Myocardial Myocardium PDGFRB gene Pathologic Pathway interactions Pericytes Physiological Platelet-Derived Growth Factor beta Receptor Play Process Proteins Proto-Oncogene Proteins c-sis Recruitment Activity Regulation Role Signal Transduction Stress Testing Training Tube Ventricular Dysfunction angiogenesis biological adaptation to stress capillary cell type heart preservation in vitro Model insight migration novel novel therapeutics paracrine postnatal pressure prevent public health relevance research study response role model stressor treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Emerging observations indicate that the processes of cardiomyocyte growth and cardiac angiogenesis must remain balanced throughout life and suggest that excess cardiac hypertrophy and/or insufficient cardiac angiogenesis in response to stress leads to impaired cardiac function, cardiomyopathy, and heart failure. An imbalance between cardiac growth and cardiac angiogenesis may play an essential role in the development and progression of multiple forms of human heart failure. Intriguingly, several recent studies indicate that the cardiomyocyte itself functions in a paracrine fashion to regulate blood vessel growth in the heart in response to stress. However, the molecular regulation of this paracrine function of cardiomyocytes (the angiogenic potential of cardiomyocytes) is not well understood. Our central hypothesis is that under conditions of stress that lead to cardiac hypertrophy, platelet derived growth factor receptor beta (PDGFR-) is an upstream regulator of the angiogenic potential of cardiomyocytes. In support of this hypothesis, we have shown that cardiomyocyte specific Pdgfrb knockout mice exposed to pressure overload stress develop cardiac dysfunction, ventricular dilatation and heart failure, associated with defective coronary microvascular function. These findings demonstrate that PDGFR- signaling is an essential and heretofore unappreciated mediator of the cardiac stress response. To further understand the role of PDGFR- signaling as a regulator of the angiogenic potential of cardiomyocytes, we will determine if cardiomyocyte PDGFR- signaling regulates coronary angiogenesis in response to pathologic stressors that lead to cardiac hypertrophy using a Pdgfrb knockout model and also via administration of anti-cancer agents whose targets include PDGFR- (Aim One). We will further determine if cardiomyocyte PDFGR- signaling is required to promote coronary angiogenesis which accompanies physiologic cardiac growth observed in early postnatal life or in adult life in response to exercise training using a Pdgfrb knockout model (Aim Two). Finally, we will determine the mechanism(s) by which PDGFR- signaling regulates the angiogenic potential of cardiomyocytes using an in vitro model of cultured cardiomyocytes in which PDGFR- is deleted. Confirmation of our overall hypothesis through the experiments proposed in this application would suggest that PDGFR- in the heart may be a novel area of concern in evaluating and treating selected forms of human heart failure, and in addition, may inform strategies to prevent and/or treat cardiotoxicity in cancer patients treated with agents that target PDGFR signaling. PUBLIC HEALTH RELEVANCE: Studies proposed in this application will seek to understand the role of platelet derived growth factor beta (PDGFR-), a protein expressed on the cell surface of a number of cell types including heart muscle cells, in the regulation of blood vessel growth in the heart during heart muscle growth which occurs as a result of a variety of stressors, some of which are directly linked to the development of heart failure. Insights gained from this study may be used to develop novel therapeutic strategies for the treatment of human heart failure due to multiple etiologies, and may also be useful to help develop strategies to prevent clinical cardiac toxicity due to anti-cancer agents that target PDGFR signaling.